Heart failure afflicts greater than 5 million people in the U.S. Alarmingly, heart failure contributes to more than 300,000 deaths per year in the U.S., with a five-year mortality of approximately 50%. Heart failure is associated with reproducible cellular changes in calcium-dependent and beta-adrenergic (beta-AR) receptor-mediated signaling pathways, which occur as the body attempts to respond to the pathophysiologic changes occurring in the failing heart. Changes in beta-AR signaling and a decrease in functional coupling of remaining beta-ARs to regulatory G-proteins occurs in heart failure. However, the extent to which beta-2-AR signaling is protective or causative in chronic heart failure (HF) is unclear. Although much is known about mechanisms of pathological remodeling in HF (re-shaping of the heart), much of the information derives from small animal models with HF produced surgically, and then defined as "chronic" after several weeks. Alternatively, investigators utilize genomic perturbation models (deletion or overexpression). The objective of this application is to define the contribution of beta-2-adrenergic- receptor signaling in the development of progressive heart failure in a chronic (greater than a year), non- ischemic, large animal model. These chronic maladaptive beta-2-ARs changes affect sarcoplasmic calcium release and ryanodine receptors; and lead to a decrement in contractile function, and an increase in caspase signaling. These subsequent changes lead to pathological remodeling and heart failure. Innovative aspects of the study include the large animal model of heart failure greater than a year in duration; the capability to combine whole-animal physiology and molecular and genetic techniques; investigation of mechanisms of maladaptive isolated, chronic beta-2-AR signaling in HF; and an investigation, in part, targeted at elucidating mechanisms of reverse remodeling in cardiac resynchronization therapy. The scientific approach will be focused on an intensive cell and molecular approach that will be combined with systems physiology. In a prolonged model of HF, we will physiologically assess these animals using methodologies utilized to evaluate human patients with chronic HF; and thereafter will be able to recreate this same pathology in isolated myocytes (ex vivo). After, identifying beta-2-ARs mediated mechanisms of HF, therapeutic strategies including cardiac resynchronization therapy (CRT), beta-1 adrenergic blockade or nonspecific beta-1-and-2 blockade will be implemented. The goal will be to attenuate pathological remodeling, maladaptive signaling, and gene regulation by correcting abnormal adrenergic signaling and calcium regulation. These interventions should lead to a reversal of pathological remodeling, and facilitate recovery from progressive heart failure. The successful completion of this research will contribute to our understanding of beta-2-ARs signaling and reverse remodeling in chronic HF, and provide a better insight into the mechanisms of CRT and beta- blocker therapy. [unreadable] [unreadable] [unreadable]